Colorectal cancer accounts to a million of new cases and more than 500,000 deaths worldwide annually and the treatment options available are far from being optimum (Parkin D M, et al., CA Cancer J Clin 2005; 55: 74-108). The curative treatment of these patients involves surgery and/or chemotherapy. Palliative chemotherapy is commonly administered for patients with advanced disease and it can significantly improve the patients' quality of life and overall survival. Pyrimidine analogue, 5-fluorouracil (5-FU), has been the method of reference for treating colorectal cancer for over four decades. However, only about 20% of patients with colorectal cancer benefit from 5-FU treatment, be it in the context of adjuvant or advanced disease treatment (Moertel C G, et al., Ann Intern Med 1995; 122: 321-6; Petrelli N, et al., J Clin Oncol 1989; 7: 1419-26). More recently, additional chemotherapeutic agents for treating these patients have been approved and are now commonly used. These include the topoisomerase I inhibitor irinotecan, the platinum compound oxaliplatin and monoclonal antibodies directed against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). These new agents have increased the percentage of patients with advanced disease with an objective response up to approximately 50% and a modest but significant improvement in their overall survival (Douillard J Y, et al., Lancet 2000; 355: 1041-7; Goldberg R M, et al., J Clin Oncol 2004; 22: 23-30; Cunningham D, et al., N Engl J Med 2004; 351: 337-45; Hurwitz H, et al., N Engl J Med 2004; 350: 2335-42; Saltz L B, et al., N Engl J Med 2000; 343: 905-14).
Based on the lack of response from half of the treated patients and the modest survival improvement of those who do respond, it is obvious that additional chemotherapeutic agents are urgently needed. Furthermore, since the different chemotherapeutic agents available today are only effective in overlapping subsets of patients, it would be very advantageous to have markers capable of distinguishing the patients who will most probably respond to each of the different agents, in an attempt to improve the clinical treatment of these patients using a more personalized approach for chemotherapeutic treatment. A number of molecular markers capable of predicting the probability of responding to these chemotherapeutic agents have been described in the last decades. The tumor expression levels of the 5-FU's target thymidylate synthase (TS), the nucleotide excision repair gene ERCC1 (excision repair cross complementing-group 1) or the mutation stage of KRAS oncogene can, for example, predict the response of 5-FU, oxaliplatin and cetuximab, respectively (Allegra C J, et al., J Clin Oncol 2009; Aschele C, et al., Cancer Treat Rev 2002; 28: 27-47; Shirota Y, et al, J Clin Oncol 2001; 19: 4298-304).
However, there has been very little progress in identifying markers capable of predicting the response to irinotecan-based treatment.